Malignant pleural mesothelioma (MPM) is a highly lethal cancer of the lining of the chest cavity. To expand our understanding of MPM, we conducted a comprehensive integrated genomic study, including the most detailed analysis of BAP1 alterations to date. We identified histology-independent molecular prognostic subsets, and defined a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity. We also report strong expression of the immune-checkpoint gene VISTA in epithelioid MPM, strikingly higher than in other solid cancers, with implications for the immune response to MPM and for its immunotherapy. Our findings highlight new avenues for further investigation of MPM biology and novel therapeutic options. Significance: Through a comprehensive integrated genomic study of 74 MPMs, we provide a deeper understanding of histology-independent determinants of aggressive behavior, define a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity, and discovered strong expression of the immune-checkpoint gene VISTA in epithelioid MPM. See related commentary by Aggarwal and Albelda, p. 1508. This article is highlighted in the In This Issue feature, p. 1494

Ovarian carcinomas represent a heterogeneous group of neoplasms consisting of separate entities with distinct risk factors, precursor lesions, pathogenesis, patterns of spread, molecular profiles, clinical course, response to chemotherapy, and outcomes. The histologic subtype and the related molecular features are essential for individualized clinical decision-making. The fifth edition of the World Health Organization classification of tumors of the female genital tract divides ovarian carcinomas into at least five main and distinct types of ovarian carcinomas: high-grade serous carcinoma, low-grade serous carcinoma, endometrioid carcinoma, clear cell carcinoma, and mucinous carcinoma. Molecular pathology has improved the knowledge of genomic landscape of ovarian carcinomas identifying peculiar alterations for every histologic subtype. It is well-known that high-grade and low-grade serous carcinomas are separate entities with entirely different morphologic and molecular characteristics. TP53 and BRCA mutations are typical of high-grade serous carcinoma, whereas BRAF and KRAS mutations frequently occur in low-grade serous carcinoma. Endometrioid and clear cell carcinomas are frequently associated with endometriosis. Endometrioid tumors are characterized by β-catenin alterations, microsatellite instability, and PTEN and POLE mutations, while ARID1A mutations occur in both endometrioid and clear cell carcinomas. Mucinous carcinomas are uncommon tumors associated with copy-number loss of CDKN2A and KRAS alterations and metastasis from other sites should always be considered in the differential diagnosis.

Imatinib has so far been the first-choice treatment in chronic myeloid leukemia with excellent results. However, only a proportion of patients achieve major molecular response – hence the need to find biological predictors of outcome to select the optimal therapeutic strategy now that more potent inhibitors are available. We investigated a panel of 20 polymorphisms in seven genes, potentially associated with the pharmacogenetics of imatinib, in a subset of 189 patients with newly diagnosed chronic myeloid leukemia enrolled in the TOPS trial. The analysis included polymorphisms in the transporters hOCT1, MDR1, ABCG2, OCTN1, and OATP1A2, and in the metabolizing genes CYP3A4 and CYP3A5. In the overall population, the OCTN1 C allele (rs1050152), a simple combination of polymorphisms in the hOCT1 gene and another combination in the genes involved in imatinib uptake were significantly associated with major molecular response. The combination of polymorphisms in imatinib uptake was also significantly associated with complete molecular response. Analyses restricted to Caucasians highlighted the significant association of MDR1 CC (rs60023214) genotype with complete molecular response. We demonstrate the usefulness of a pharmacogenetic approach for stratifying patients with chronic myeloid leukemia according to their likelihood of achieving a major or complete molecular response to imatinib. This represents an attractive opportunity for therapy optimization, worth testing in clinical trials.

Quadruple wild-type (WT) gastrointestinal stromal tumor (GIST) is a genomic subgroup lacking KIT/PDGFRA/RAS pathway mutations, with an intact succinate dehydrogenase (SDH) complex. The aim of this work is to perform a wide comprehensive genomic study on quadruple WT GIST to improve the characterization of these patients. We selected 14 clinical cases of quadruple WT GIST, of which nine cases showed sufficient DNA quality for whole exome sequencing (WES). NF1 alterations were identified directly by WES. Gene expression from whole transcriptome sequencing (WTS) and miRNA profiling were performed using fresh-frozen, quadruple WT GIST tissue specimens and compared with SDH and KIT/PDGFRA-mutant GIST. WES identified an average of 18 somatic mutations per sample. The most relevant somatic oncogenic mutations identified were in TP53, MEN1, MAX, FGF1R, CHD4, and CTDNN2. No somatic alterations in NF1 were identified in the analyzed cohort. A total of 247 mRNA transcripts and 66 miRNAs were differentially expressed specifically in quadruple WT GIST. Overexpression of specific molecular markers (COL22A1 and CALCRL) and genes involved in neural and neuroendocrine lineage (ASCL1, Family B GPCRs) were detected and further supported by predicted miRNA target analysis. Quadruple WT GIST show a specific genetic signature that deviates significantly from that of KIT/PDGFRA-mutant and SDH-mutant GIST. Mutations in MEN1 and MAX genes, a neural-committed phenotype and upregulation of the master neuroendocrine regulator ASCL1, support a genetic similarity with neuroendocrine tumors, with whom they also share the great variability in oncogenic driver genes. Implications: This study provides novel insights into the biology of quadruple WT GIST that potentially resembles neuroendocrine tumors and should promote the development of specific therapeutic approaches. Mol Cancer Res; 15(5); 553–62. ©2017 AACR.